Title: Role of HDAC2 as a modulator of aging and Alzheimer?s disease phenotypes in stem-cell derived neurons. Project Summary/Abstract Brain aging is a significant contributor to many neurodegenerative disorders, including Alzheimer?s disease (AD), and is tightly regulated by epigenetic mechanisms. Until recently, studying human neural aging has been challenging due to the relative inaccessibility of living brain tissue. Recent advances in cellular reprogramming, either by inducing stem cells from somatic cells and differentiating to a neural lineage or by direct transdifferentiation of somatic cells to neurons, have been transformative. However, a global understanding of epigenetic changes and the contribution of age in a human cellular model of AD is lacking. Recent studies demonstrate that the epigenetic regulator histone deacetylase 2 (HDAC2) is abnormally elevated in AD and aged brains. The applicant, Dr. Jessica E. Young, is proposing to combine her considerable experience in stem cell biology and Alzheimer?s disease modeling with mentorship in aging biology, functional genomics, and neuronal mitochondrial biology to test the overarching hypothesis that HDAC2 is a driver of cellular age in human neurons and contributes to AD-relevant phenotypes. This project will ask three critical questions: 1) Does the epigenetic regulator HDAC2 drive epigenomic and transcriptomic changes related to aging human neurons? 2) Does modulation of HDAC2 expression alter cellular aging phenotypes in human neurons? 3) Does modulation of HDAC2 expression affect cellular phenotypes relevant to AD pathology in human neurons? To address this questions, Dr. Young will pursue functional genomic and cell biological experiments based on modulation of HDAC2 expression in hiPSC-derived and transdifferentiated human neurons. This work will advance understanding on specific pathways that link aging with AD pathogenesis and evaluate the utility of HDAC2 as a tool to develop age-relevant AD in vitro studies. Dr. Young is a new Assistant Professor in the Department of Pathology and a member of the Institute for Stem Cell and Regenerative Medicine at the University of Washington. She will devote 75% of her time to research under this award and will supplement her research with didactic training in aging biology, neuropathology, and epigenomic and transcriptomic analyses. This training will be comprised of 1) departmental and university courses, 2) seminars and journal clubs 3) responsible conduct of research courses and 4) national and international conferences. Dr. Young will be mentored by Dr. Peter Rabinovitch, Dr. Jay Shendure, Dr. C.Dirk Keene, and Dr. Richard Morrison at the University of Washington. These established scientists are renowned experts in biology of aging, functional genomics, neuropathology, and neuronal mitochondrial biology, respectively. Dr. Young has met with each of her mentors to discuss this project and will continue to meet with them at regular intervals (specified in mentorship letters) during the course of this award. She is expected to produce manuscripts as corresponding or co-corresponding author and be competitive for R-level grants during the course of this award. This project will integrate Dr. Young?s current expertise with additional training to develop a well-rounded, independent research program.